Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

Abstract

Lamellar ichthyosis (LI, OMIM no. 242300) is a severe autosomal recessive genodermatosis with an estimated prevalence of 1:200,000. LI represents one end of the spectrum of congenital recessive ichthyosis (CRI). Mutations in the gene for transglutaminase-1 (TGM1) are responsible for many cases of LI and occur throughout the coding sequence of the gene. Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message. We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation. A mutation at this same site occurs in the majority of Norwegian patients as a founder effect. In our ethnically diverse patient population, none of whom have known Norwegian ancestry, haplotype analysis of the TGM1 chromosomal region also suggested the existence of a founder effect. Comparison of the common haplotype in our data with the Norwegian data showed that 2/7 of our splice acceptor site mutation chromosomes had the full reported Norwegian haplotype, and the remaining five chromosomes exhibited recombination at the most distal marker studied. History, family origins, and haplotype analysis suggested that the mutation originally arose on a German background and was introduced into Norway around 800-1000 AD. We also found a limited correlation between genotype and phenotype in our study, with the four homozygous patients having less severe disease than many of the heterozygotes, and no patient with a splice acceptor site mutation having erythroderma or a congenital ichthyosiform erythroderma phenotype.

Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia: Clinical Characteristics and Novel and Recurrent Mutations in 132 Patients

“…The point mutation c.877-2A>G was identified in 14% of alleles associated with LI/CIE, mainly in the Swedish patients. This mutation has also been described from several other countries (37,38,40,41,(48)(49)(50)(51)(52)(53) and is reported as a founder mutation in Norway (49), located close to Sweden. The p.Ser358Arg mutation was originally identified in a Swedish family (28) and there is no report of this mutation outside Sweden and Norway (unpublished data), which suggests a local founder mutation.…”

Molecular genetics of the ichthyoses

“…At least five different genes have been implicated in its pathogenesis, including TGM1 at chromosomes 14q11.2 [Huber et al, 1995], the lipoxygenase genes ALOX12B and ALOXE3 on 17p13.1 [Jobard et al, 2002], the loricrin gene on 1q21 [Matsumoto et al, 2001], and a yet to be unveiled gene on 19p13.1-p13.2 [Virolainen et al, 2000]. A subset of patients, especially those with less intense redness of the skin, carry mutations in TGM1 leading to transglutaminase-1 deficiency with ensuing abnormal formation of the cornified cell envelope and perturbed barrier function of the skin as discussed above [Huber et al, 1995;Hennies et al, 1998;Shevchenko et al, 2000]. However, no definitive genotype-phenotype correlations have been established yet.…”

“…Genotypephenotype correlations revealed that TGM1 mutations are usually associated with the features of 'classical,' nonerythrodermic LI, while only some patients with mild or moderate erythroderma, white, gray, or small scales carry TGM1 defects [Hennies et al, 1998;Laiho et al, 1999;Shevchenko et al, 2000]. The identification of a major disease gene in LI paved the road for DNAbased molecular genetic testing.…”

“…LI has been mapped to at least 3 genetic loci, including chromosomes 14q11.2 (LI-1), 2q33-q35 (LI-2), and [Pigg et al, 1998;Shevchenko et al, 2000]. Genotypephenotype correlations revealed that TGM1 mutations are usually associated with the features of 'classical,' nonerythrodermic LI, while only some patients with mild or moderate erythroderma, white, gray, or small scales carry TGM1 defects [Hennies et al, 1998;Laiho et al, 1999;Shevchenko et al, 2000].…”

Ictiosis congénitas autosómicas recesivas

“…La mutación más frecuente es la c.877-2A > G, que ha sido encontrada en el 34% de los alelos mutados descritos hasta la fecha 52 . La alta frecuencia de esta mutación en países como Estados Unidos y Noruega se debe a un efecto fundador 12,53 . La segunda mutación más frecuente es la p.Arg142His.…”